Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Isolated segments of the guinea-pig small intestine were vascularly perfused and the release of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) into the portal venous effluent determined by high pressure liquid chromatography with electrochemical detection. Release of acetylcholine from isolated superfused intestinal segments was determined as outflow of [3H]radioactivity from preparations preincubated with [3H]choline. Cisplatin (3 microM) increased the outflow of 5-HT and 5-HIAA by about 90%. At 30 and 100 microM cisplatin decreased the outflow of 5-HT and its metabolite by 40%-50%. The stimulatory effect of cisplatin was consistently observed only when the bicarbonate-phosphate buffer of the Tyrode's solution was replaced by HEPES-buffer. The stimulatory effect of cisplatin was abolished in the absence of extracellular calcium or presence of tetrodotoxin (1 microM). The stimulatory effect of cisplatin was also prevented by hexamethonium (100 microM) or scopolamine (100 nM). The 5-HT3 receptor antagonists ondansetron and ICS 205-930 in concentrations as low as 1 pM also abolished the stimulatory effect of cisplatin. The 5-HT3 receptor antagonist MDL 72222 prevented the stimulatory effect of cisplatin only at a concentration of 1 microM. None of the 5-HT3 receptor antagonists alone significantly altered the outflow of 5-HT and 5-HIAA. Cisplatin (3 microM) enhanced the outflow of [3H]radioactivity from intestinal segments and caused longitudinal muscle contractions that were abolished by 100 nM scopolamine. In conclusion, cisplatin, at concentrations which occur during anti-cancer therapy in humans and induce emesis, increases the release of 5-HT from the enterochromaffin cells of the small intestine of the guinea-pig.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cisplatin increases the release of 5-hydroxytryptamine (5-HT) from the isolated vascularly perfused small intestine of the guinea-pig: involvement of 5-HT3 receptors. 171 32

Emesis in chemotherapy containing Cisplatinum (DDP) is still a therapeutical dilemma. Emesis and nausea cause the cessation of a potential curative therapy in up to 10% of patients treated with DDP. We studied the antiemetic effectiveness of the selective Serotonin (5HT3)-receptor-antagonist Ondansetron (GR 38032F, Glaxo) in patients receiving high dose platinum chemotherapy. All patients suffered from severe emesis and were refractory to any standard antiemetic regimen (Metoclopramid). We studied the efficacy of the new drug against acute and delayed emesis following platinum chemotherapy. All adverse events are listed. Thirty four courses (n = 17 patients) of a platinum-containing regimen were analyzed so far. A sufficient antiemetic efficacy was observed in 56% of the courses. In 32 of 34 course (94%) the patients preferred the new drug compared with the standard antiemetic regime (Metoclopramid). In most cases only minor adverse events--which do not require any medical therapy--occurred. The most common adverse events were headache, constipation, dry mouth, abdominal discomfort and elevation of liver enzyme level without any clinical symptoms. One patient needed bowel surgery for severe constipation based on widespread intra-abdominal carcinosis.
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PMID:[Refractory vomiting with cisplatin therapy. Prospective study with the serotonin receptor antagonist GR 38032F]. 215 May 51

1. The purpose of the present study was to identify and investigate the role of 5-hydroxytryptamine3 (5-HT3) receptors in the area postrema in the control of cisplatin-induced emesis in the ferret. 2. Homogenate binding and autoradiography experiments using the high affinity 5-HT3 receptor ligand, [3H]-GR65630, identified the presence of a high concentration of 5-HT3 receptors in the area postrema of the ferret. 3. Intraperitoneal injection of the 5-HT3 receptor antagonists, GR38032F, GR65630A and MDL72222, at doses of 1, 0.1 and 1 mg kg-1 respectively, inhibited emesis induced by cisplatin, 9 mg kg-1 i.p. 4. Discrete injection of low doses of the 5-HT3 receptor antagonists directly into the area postrema region also inhibited cisplatin-induced (9 mg kg-1 i.p.) emesis. The dose ranges used were: GR38032F, 0.01-1 microgram; GR65630A, 0.001-0.1 microgram; MDL72222, 0.1-10 micrograms. 5. Cisplatin-induced emesis was not inhibited by discrete injection of ketanserin (30 micrograms) or methiothepin (30 micrograms) into the area postrema. Injection of the 5-HT3 receptor agonist, 2-methyl-5-HT, directly into the area postrema produced an incomplete emetic response. 6. These results confirm a role of 5-HT, and in particular 5-HT3 receptors, in the control of cisplatin-induced emesis, and show that at least one functional site for these receptors in modulating the emetic response is the area postrema, the locus of the chemoreceptor trigger zone.
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PMID:5-HT3 receptor antagonists injected into the area postrema inhibit cisplatin-induced emesis in the ferret. 272 Mar 10

The effect of Y-25130 on gastric emptying of nutrient test meals (solid chow) was examined in mice. In a dose range of 0.01-1 mg/kg, p.o., Y-25130 significantly accelerated gastric emptying of solid meals in a dose-dependent manner, at an ED30 of 0.021 mg/kg. Other 5-hydroxytryptamine3 receptor antagonists and prokinetic agents having 5-hydroxytryptamine3 receptor antagonistic properties accelerated the emptying of solid meals in the following rank order of potency: Y-25130 = granisetron > or = tropisetron > ondansetron > cisapride > metoclopramide. The acceleration of the gastric emptying showed a good correlation with the antagonistic potencies of these compounds on 5-hydroxytryptamine3 receptors, determined by the inhibition test of the von Bezold-Jarisch reflex in anesthetized rats (r2 = 0.99). Domperidone (1 and 10 mg/kg, p.o.) and trimebutine (10 and 100 mg/kg, p.o.) failed to increase the rate of emptying from the stomach. Cisplatin (30 mg/kg, i.p.), a chemotherapeutic agent, significantly delayed the gastric emptying of solid meals, and Y-25130 (0.1-1 mg/kg, p.o.) prevented such a delay in emptying in a dose-dependent manner. These results suggest that Y-25130 accelerates the gastric emptying in mice by antagonism of the 5-hydroxytryptamine3 receptor.
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PMID:Effect of Y-25130, a selective 5-hydroxytryptamine3 receptor antagonist, on gastric emptying in mice. 762 86

In 46 weaned piglets we surgically implanted a cannula in the jugular vein and electrodes for ECG and EMG recordings. After a 4- to 5-day recovery, piglets were hydrated, then dosed with cisplatin (5.5 mg/kg i.v.) and recorded continuously for the next 60 h. Thirteen piglets (i.e., controls) received only cisplatin. Twenty-three other piglets received, 15 min before cisplatin, an i.v. injection of granisetron (0.25, 0.5, 2 or 7 mg/kg) or ondansetron (0.5, 2 or 7 mg/kg). Ten other piglets received, in addition to cisplatin, multiple injections of granisetron (1 mg/kg) and ondansetron (3.5 mg/kg). All control piglets exhibited both acute and delayed emesis. The first vomiting occurred with a latency of 2.13 +/- 0.82 hr after cisplatin administration; emetic intensity reached a peak (5 vomits/hr) within 2 hr and then decreased rapidly. No vomiting was observed between the 16th and 18th hr. The mean number of vomits during the first 16th was 18.4 +/- 2. Delayed emesis started at the 18th hr and lasted until the 58th hr. The mean number of vomits during the whole of the delayed phase was 9.6 +/- 2.4; the highest emetic intensity (1.2 vomit/hr) occurred between the 21th and the 22th hr. Pretreatment with a 5-HT3 receptor antagonist increased significantly the latency of the first emetic event in a dose-dependent manner. However, the severity of the acute phase was reduced significantly only with granisetron at the dose of 7 mg/kg, although the severity of the delayed phase remained unchanged, irrespective of the dose of granisetron. Three about five piglets treated repeatedly with granisetron did not vomit throughout the chemotherapy course. In contrast, no complete control was observed with repetitive injections of ondansetron. Cisplatin inducing both acute and delayed vomiting in the piglet without any lethality; this animal is a suitable model in which to study the pathogenesis of delayed emesis.
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PMID:The piglet as a suitable animal model for studying the delayed phase of cisplatin-induced emesis. 763 59

The emetic effects of copper sulfate and cisplatin and the potential involvement of vagal afferent fibers and 5-HT3 receptors in the emesis were investigated in cynomolgus monkeys. Retching and vomiting induced by both oral (100 mg/kg) and intravenous (20 mg/kg) copper sulfate were inhibited markedly by abdominal vagotomy. Furthermore, the emetic response induced by oral copper sulfate was strongly inhibited by intravenous ICS 205-930 (0.1 mg/kg), a 5-HT3 receptor antagonist. Cisplatin (3 mg/kg, i.v.) caused severe retching and vomiting, and the number of emetic responses was much greater than that in other species. The emetic response induced by cisplatin was inhibited markedly by abdominal vagotomy or concurrent administration of ICS 205-930 (3 x 0.1 mg/kg, i.v.). These results suggest that the monkey is more sensitive to cisplatin than other species and that the vagal afferent terminals and 5-HT3 receptors play an important role in the emetic response induced by copper sulfate and cisplatin.
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PMID:Involvement of 5-HT3 receptors and vagal afferents in copper sulfate- and cisplatin-induced emesis in monkeys. 828 15

We investigated the involvement of peripheral and central serotonin (5-HT)3 receptors in cisplatin- and 5-HT3 receptor agonist-induced emesis in ferrets. Cisplatin (10 mg/kg i.v.)-induced emesis was inhibited by intravenous YM060 (0.003-0.1 microgram/kg). A highly selective and potent 5-HT3 receptor agonist, m-chlorophenylbiguanide (1-10 mg/kg i.p.), dose dependently elicited emesis an effect which was inhibited by YM060 (0.003-0.3 microgram/kg i.v.). Vagotomy markedly reduced this emesis, and the combination of abdominal vagotomy and greater splanchnicectomy abolished emesis. Lesion of greater splanchnic nerves alone did not markedly inhibit emesis. Intracerebroventricularly (4th ventricle) administered YM060 inhibited cisplatin- and m-chlorophenylbiguanide-induced emesis only at higher doses (0.01-0.1 and 0.01-0.03 microgram, respectively). Intracerebroventricularly (4th ventricle) administered m-chlorophenylbiguanide (30-100 micrograms) produced only a weak retching response. These results indicate that stimulation of abdominal vagal afferent nerves via peripheral 5-HT3 receptors is important for triggering cisplatin- and m-chlorophenylbiguanide-induced emesis in ferrets.
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PMID:Mechanisms of cisplatin- and m-chlorophenylbiguanide-induced emesis in ferrets. 840 4

Emesis is a common side effect of chemotherapeutic drugs. Cisplatin, nitrogen mustard and dacarbazine induce increases in urinary 5-hydroxyindoleacetic acid (5-HIAA) in parallel with the development of the period of emesis which is sensitive to 5-HT3 receptor antagonists ('acute emesis'). It is suggested that these cytotoxics release serotonin from enterochromaffin cells, which then acts on 5-HT3 receptors to trigger the emetic response. Cyclophosphamide, on the other hand, induces a modest emetic response, partly sensitive to 5-HT3 receptor antagonists, but not associated with increases in urinary 5-HIAA. It is suggested that cyclophosphamide-induced emesis is not mediated by the release of serotonin from enterochromaffin cells. Although after high-dose cisplatin most emesis is sensitive to 5-HT3 receptor antagonists, patients often present a milder, although more prolonged form of emesis which is mostly resistant to 5-HT3 receptor antagonists (also known as 'delayed emesis'). This form of emesis is not associated with increases in urinary 5-HIAA (not due to serotonin released from the enterochromaffin cells). Treatment with p-chlorophenylalanine (a serotonin synthesis inhibitor) inhibited cisplatin-induced emesis and cisplatin-induced increases in urinary 5-HIAA excretion. In summary, these results indicate that in human patients, serotonin plays a fundamental role in chemotherapy-induced emesis. Serotonin released from enterochromaffin cells seems to mediate emesis sensitive to 5-HT3 receptor antagonists induced by cisplatin, dacarbazine and nitrogen mustard. Emesis sensitive to 5-HT3 receptor antagonists associated with cyclophosphamide treatment, is not mediated by the release of serotonin from enterochromaffin cells by the cytotoxic. Therefore, cyclophosphamide could induce serotonin release either from enteric serotonin nerves or from the CNS. Cisplatin-induced emesis resistant to 5-HT3 receptor antagonists ('delayed emesis') is not mediated by serotonin released from enterochromaffin cells.
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PMID:Serotonin mechanisms in chemotherapy-induced emesis in cancer patients. 869 46

In order to elucidate possible male/female differences in emesis, the effects of various emetogenic drugs (cisplatin, copper sulfate, veratrine, nicotine, serotonin) and motion stimulus were compared between male and female Suncus murinus. Cisplatin (IP), nicotine (SC), veratrine (SC) and copper sulfate (PO) induced dose-dependent emesis in either sex, and there was no apparent difference in estimated ED50 values. However, male animals tended to be more susceptible to serotonin-induced emesis. The ID50 values for tropisetron, a 5-HT3 receptor antagonist, to block serotonin-induced emesis were also similar between male and female animals. However, tropisetron was less effective against cisplatin-induced emesis in females. Therefore, cisplatin may release more serotonin to induce emesis in females. Reciprocal shaking (horizontal oscillation 40 mm, frequency 0.5 to 2.0 Hz, duration 5 min) induced more frequent emesis in male animals, and the latency to the first vomit was shorter in males than in females. These results suggest that there is substantial sex-dependent difference in the emetic responses and male animals are in general more susceptible. These results are discussed in the light of similar studies in man.
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PMID:Male/female differences in drug-induced emesis and motion sickness in Suncus murinus. 925 99

Cisplatin causes nausea, vomiting and inhibition of gastric emptying. We have demonstrated the antiemetic effect of the acetone and ethanolic extract of ginger (Zingiber officinale, Roscoe, Zingiberacae) against cisplatin-induced emesis in dogs. In the present study, the acetone and 50% ethanolic extract of ginger in the doses of 100, 200 and 500 mg/kg (p.o.) and ginger juice, in the doses of 2 and 4 ml/kg, were investigated against cisplatin effect on gastric emptying in rats. All three ginger preparations significantly reversed cisplatin-induced delay in gastric emptying. The ginger juice and acetone extract were more effective than the 50% ethanolic extract. The reversal produced by the ginger acetone extract was similar to that caused by the 5-HT3 receptor antagonist ondansetron; however, ginger juice produced better reversal than ondansetron. Therefore, ginger, an antiemetic for cancer chemotherapy, may also be useful in improving the gastrointestinal side effects of cancer chemotherapy.
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PMID:Reversal of cisplatin-induced delay in gastric emptying in rats by ginger (Zingiber officinale). 972 Jun 11


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